The patient with cancer faces two threats: the cancer itself and the cancer treatment. An unwelcome organism has arisen from within and it needs to be removed or dissolved. One of the personal costs of cancer treatment is the adverse effect of treatment, and it is among the highest price tags in all of medicine. The patient wants to know, “what will the cancer do to me if it is not treated” and “what will the treatment do to me?” The physician uses different terms to ask the same questions: what are the odds of survival and toxicity with each treatment option. In clinical terms, both parties want to know the impact of cancer and its treatment on the “host”. Both threats can result in illness or death.
The management of cancer often involves making choices among various treatment options, some of which are more toxic than others. The degree of “aggressiveness” of a treatment program is currently ill defined, but is generally proportional to the amount of toxicity. The “tolerance” of a regimen is a general perception by the clinician relative to other treatments for the same category of patients, and may focus on a single treatment-limiting organ, e.g., bone marrow. In general, the greater the threat of the disease to life, organ function or severity of discomfort from the disease, the more risk or ill effects one is willing to consider in order to counter the disease. An attempt is made to match treatment intensity to the severity of disease, but there are no suitable metrics to guide that decision-making. Currently, in the art there does not exist a method to ascertain if the toxicity of a given treatment is “acceptable” or not. Accordingly, no formal numbers can be applied to calculate a so-called “therapeutic ratio” relating the treatment effectiveness to the treatment toxicity.
Oncology is a unique and suitable model for development of better adverse effects reporting methods as well as a classification system for toxicity. It is one of the only fields of medicine where not only are many of the agents highly toxic, but they are used in combination, at times with radiation and surgery, generating multiple significant toxicities in the same patient. For non-oncology drugs, a given patient may experience 1 or 2 side effects at most, and these are usually mild in nature. Drug warning labels generally contain a list of possible adverse effects, with frequencies rarely over 10-20%. Severe side effects are usually rare, and life-threatening ones are extremely rare. In oncology, it is not uncommon to see rates of grade 3-4 effects in the 50-60% range with a conclusion that the regimen was “well tolerated”. Death rates of 1-3% are routinely accepted in aggressive regimens, and mortality has approached 30% in some bone marrow transplant studies.
Modern cancer therapy employs multiple aggressive treatment modalities associated with significant short and long-term morbidity. Balancing the cancer itself and the cancer treatment for a net therapeutic benefit is a judgment that requires reliable and readily interpretable information regarding both survival and toxicity. Interpreting toxicity information in oncology is a difficult task, for both the patient and the physician. For even a single trial, there is a large amount of toxicity information to digest, and no associated method of summarizing this data into a readily interpretable and useful statement. This is aggravated by gaps and inconsistencies in current reporting methods that make it nearly impossible to compare adverse outcomes between studies or among treatment options. This is in sharp contract to the ability to describe prognosis, which includes multiple well-defined endpoints and sophisticated analytical tools. Scientists have developed a common language to characterize and communicate the wonders of the human genome, but we cannot effectively communicate to our patients the full scope of risk from cancer treatment. As such, the adverse effects reporting process is comparatively under-developed, and there has been no organized effort to advance it. At a practical level, only half of the therapeutic ratio is defined, thereby limiting the ability to make informed judgments about risks and benefits of treatment protocols.
Quantifying the negative impact of cancer treatment on health has been difficult. One major factor is the myriad expressions of ill effects. As currently codified in the National Cancer Institute-Common Terminology Criteria (NCI-CTC v 3.0), there are more than 500 distinctly recognizable types of injury or symptoms, each with 4 grades of severity, resulting in more than 2000 definable ill effects. The duration and number of episodes of each event adds to the perception of toxicity burden. Some ill effects occur in a repetitive fashion with each cycle of treatment and others can cause permanent changes, which may last a lifetime.
The TNM (Tumor, Nodes, Metastases) tumor staging system was developed more than 40 years ago. The TNM system gauges the severity of cancer on an escalating scale. It has been widely adopted and used to stage more than 30 million cancer patients in the U.S. since its inception. It is routinely applied to the majority of solid tumors and more than 70% of all cancers. More than 500,000 patients in the U.S. are staged annually. In 1990 it was harmonized with the international staging system (IUCC) to represent one of the most valuable tools in cancer epidemiology and treatment-related decision-making worldwide. It has undergone periodic revisions as new technologies or interventions have altered outcomes.
The TNM system has three components or domains. T (tumor) represents the local extent and invasiveness of the primary cancer. N (node) represents the extent of nodal spread, and M (metastasis) represents the presence or absence of metastatic disease. Limiting it to three simple factors is in large part why the TNM system has been so well adopted and enduring. However, each tumor site uses different T and N criteria, based on their own unique behavior. Indeed, the specific rules and terms for staging each site are quite distinct and elaborate, requiring a large staging manual and special training. Cancers may be staged clinically or surgically (pathologically) or a mixture of the two.
The TNM system also has limitations, which have been recognized. This system reflects only the anatomic extent of disease and does not include other known prognostic factors such as histological type, grade, age, sex, co-morbid illness or duration of symptoms. It does not include biologic factors, which may also be prognostic. Each T, N, and M domain reflects a conceptual progression of cancer by estimating its true anatomic extent. It does not include direct measures of the number of cancer cells or any direct measures of the impact of the cancer on the host (symptoms or other effects). Although it is generally prognostic for survival and tumor control, it is actually only a rough estimate of the extent of cancer. Additionally, the TNM system does not communicate and forecast the extent of toxicity of a given treatment program.
Accordingly, what is needed in the art is a method for summarizing the complexities of the toxicity experience associated with a variety of disease conditions, including cancer. Such a method would provide for the reduction of a large quantity of toxicity data from a given treatment program into a summary statement which captures the important features of global or aggregate toxicity burden. Such a method should have wide applications to many facets of oncology and other fields of medicine.
However, in view of the prior art considered as a whole at the time the present invention was made, it was not obvious to those of ordinary skill in the pertinent art how the identified need could be fulfilled.